Aging is a major risk factor of human cancers. Our project is to elucidate molecular mechanisms of aging and cancer using cellular and animal models. We have shown that normal human cells have telomerase-dependent and independent pathways for cellular senescence, which both serve as a tumor suppressive mechanism. The senescence genes on chromosome 3p21 (a transcriptional repressor of the telomerase hTERT gene) and chromosome 1q42.3 (which functions independently of telomerase regulation) are to be cloned by the positional and functional cloning methods. To understand a link between cellular aging and organismal aging, we study SIRTs, human homologs of the yeast/worm longevity gene Sir-2 encoding a NAD-dependent protein deacetylase. Our data suggest the more complex regulation of aging processes in humans than in yeast or worms and multiple functions of human SIRT proteins at different cellular locations (i.e., nucleus, nucleolus, cytoplasm and mitochondria). We have found that DNA double-strand breaks (DSB) accumulate in mammalian cells during both cellular senescence and in vivo aging, providing important insight into the mechanism by which cellular senescence contribute to organismal aging. We are also examining how various local or systemic conditions (e.g., hypoxia, oxidative stress, obesity, calorie intake) affect the above-mentioned pathways/factors to regulate human aging and carcinogenesis processes.